Synergistic Antitumor Activity of Curcumin and the PARP1 Inhibitor PJ34 in Platinum-Sensitive and Resistant Ovarian Cancer Cells.

BACKGROUND/OBJECTIVES: Ovarian cancer remains a highly lethal malignancy, largely due to the development of therapeutic resistance, particularly in advanced disease. Combination strategies targeting complementary molecular pathways may enhance antitumor efficacy and help overcome resistance. The present study aimed to systematically evaluate the anticancer effects of the PARP1 inhibitor PJ34 and the natural polyphenol curcumin, administered alone and in combination, in platinum-sensitive and relatively platinum-resistant ovarian cancer models, with an emphasis on quantitative synergy assessment and functionally supported, hypothesis-generating mechanistic insight. MATERIALS AND METHODS: Cell viability was evaluated using the MTT assay, and IC(50) values were derived from dose-response curves. Drug interactions were quantitatively analyzed using the Chou-Talalay method, including combination index (CI) and dose reduction index (DRI) calculations. Intracellular reactive oxygen species (ROS) levels were measured using DCFH-DA-based assays. Cell migration was assessed using scratch-wound assays. Apoptosis was evaluated using Annexin V/PI flow cytometry, caspase-3 activity assays, and quantitative real-time PCR (RT-qPCR) analysis of apoptosis-related genes (Bax, Bcl-2, Caspase-3, Caspase-9, and p53). To further validate the findings under physiologically relevant conditions, three-dimensional (3D) tumor spheroid models were employed, and ROS involvement was functionally interrogated using N-acetyl-L-cysteine (NAC) rescue experiments to assess ROS-associated contributions rather than direct causality. RESULTS: PJ34 and curcumin each reduced cell viability in a dose-dependent manner, whereas their combination produced a synergistic antiproliferative effect with reduced IC(50) values. Synergism was particularly pronounced in relatively platinum-resistant SKOV-3 cells. Combination treatment significantly enhanced regulated apoptotic cell death, as demonstrated by increased apoptotic fractions, elevated caspase-3 activity, and an increased Bax/Bcl-2 ratio, with minimal necrosis. While PJ34 moderately increased intracellular ROS levels and curcumin reduced oxidative stress, the combination was associated with the normalization of ROS levels to near-control values. In 3D tumor spheroid models, combined treatment induced marked spheroid shrinkage, loss of structural integrity, and reduced viability, indicating a preservation of synergistic cytotoxic effects beyond two-dimensional (2D) conditions. NAC pretreatment partially attenuated, but did not fully rescue, the cytotoxic effects of the combination, indicating a ROS-associated, but not exclusively ROS-dependent, mechanism of action. In addition, the combination markedly inhibited cell migration in both ovarian cancer cell lines. CONCLUSIONS: This preclinical provides evidence that combined PARP1 inhibition and curcumin treatment can exert synergistic antitumor effects in ovarian cancer models, including relatively platinum-resistant disease, through the coordinated suppression of proliferation, induction of regulated apoptosis, and inhibition of migration. The integration of quantitative synergy analysis, 3D spheroid validation, and ROS-rescue experiments provides functionally supported, hypothesis-generating mechanistic insight and supports further evaluation of PARP inhibitor-curcumin combinations as a mechanistic proof-of-concept in advanced preclinical models.